Clinical research of drug-coated balloon after rotational atherectomy for severe coronary artery calcification

Background Current research results show that drug-coated balloons (DCB) have unique advantages in the treatment of in-stent restenosis, small vessel disease, bifurcation lesions, and de novo lesions, but the data regarding rotational atherectomy (RA) followed by DCB treatment in calcified lesions, especially severe coronary artery calcification (CAC), are limited. Methods A retrospective study was conducted on 318 individuals with severe CAC who underwent RA-assisted PCI at the First Affiliated Hospital of Zhengzhou University from May 2018 to July 2021. Among them, 57 patients (RA/DCB group) were treated with DCB, and 261 patients (RA/DES group) were treated with drug-eluting stents (DES). The two groups' clinical baseline data, lesion characteristics, intraoperative complications, in-hospital adverse events, and major adverse cardiovascular and cerebrovascular events (MACCE) were compared throughout the follow-up period. Results The baseline clinical data, intraoperative complications, and in-hospital adverse events were not significantly different between the two groups. The anatomical categories in the RA/DES group were more complex and included left main coronary disease, bifurcation disease, and multivessel disease. Although target lesion revascularization (13.79% vs. 7.02%) and MACCE (18.77% vs. 12.28%) occurred more frequently in the RA/DES group than in the RA/DCB group, there was no statistically significant difference (p > 0.05). Multivariate Cox regression analysis showed that bifurcation lesions (HR 2.284, 95% CI 1.063–4.908, p = 0.034), total length of DCB/DES (HR 1.023, 95% CI 1.005–1.047, p = 0.014) and SYNTAX score (HR 1.047, 95% CI 1.013–1.082, p = 0.006) were independent risk factors for MACCE during the follow-up period. Conclusion Drug-coated balloon treatment after rotational atherectomy appears safe and effective in selected severe coronary artery calcification.


Introduction
Even in the era of new-generation drug-eluting stents (DES), severe coronary artery calcification (CAC) remains a significant challenge for percutaneous coronary intervention (PCI) [1]. CAC is difficult to adequately predilate due to resistant plaque burden and surface irregularities, which may result in failed device delivery or incomplete stent expansion. Moreover, calcified plaques could increase technical difficulties and *Correspondence: Guoju Sun heart815@126.com Department of Cardiovascular Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China postoperative complications such as restenosis and thrombosis [2]. Therefore, adequate lesion preparation is a prerequisite for severely calcified lesions. Rotational atherectomy (RA) is the most widely used approach to modify the physical attributes of calcified plaques in preparation for angioplasty and stent deployment and subsequently optimize postprocedural results [3]. RA followed by DES implantation is currently the standard PCI strategy for severe CAC. Drug-coated balloons (DCB) provide an alternative treatment strategy for coronary artery disease by homogeneously releasing antiproliferative drugs to the lesion site during single balloon inflation and carry several anticipated benefits over DESs, including the absence of metallic stents and shorter duration of dual antiplatelet therapy (DAPT) [4]. Furthermore, DCBs show potential applications in some anatomical scenarios. These include in-stent restenosis, bifurcations, and small vessels, where stenting can lead to poor outcomes [5]. For severely calcified lesions, using RA prior to DCB therapy is thought to reduce the calcification burden and thus improve drug penetration into the vessel wall. Due to the lack of clinical studies, it is unclear whether RA followed by DCB implantation can be used as an alternative treatment strategy for severely calcified lesions. This study aimed to compare the efficacy and safety of RA/ DCB and RA/DES in treating severe CAC and provide new evidence for addressing this stent-less strategy.

Study population
From May 2018 to July 2021, consecutive patients who underwent RA followed by DCB or DES at the First Affiliated Hospital of Zhengzhou University (Henan, China) were enrolled. Only patients with severe CAC were eligible for the study, defined as radiopacities noted without cardiac motion before contrast injection and generally involving both sides of the arterial wall. The exclusion criteria were as follows: (1). Myocardial infarction within four weeks; (2). Unstable hemodynamics or cardiogenic shock; (3). Limited long-term prognosis due to other conditions; (4). Coronary artery bypass graft stenoses; (5). Lesion angulation > 90°; (6) Lesions used DES and DCB simultaneously. After exclusion, 318 patients who matched the eligibility criteria were grouped into the DES (n = 57) and DCB (n = 261) groups and then compared retrospectively.
This retrospective study complied with the Declaration of Helsinki and was approved by the ethics committee of The First Affiliated Hospital of Zhengzhou University.

Interventional procedures
Pre-and post-PCI, all patients were treated with dual antiplatelet therapy (DAPT) with oral aspirin (100 mg once daily) and clopidogrel (75 mg once daily) or ticagrelor (90 mg twice daily). In the case of emergent PCI, aspirin was administered at loading doses of 300 mg, and clopidogrel or ticagrelor was administered at 600 and 180 mg, respectively. The initial dosage of heparin (100 IU/kg) was administered before the procedure, and additional dosages were given to maintain an activated clotting time (ACT) > 300 s. RA was performed using the Rotablator ™ (Boston Scientific, USA). The rotational speed ranged between 135,000 and 180,000 rpm, and the burr/vessel ratio was recommended at 0.4-0.6. Each RA time was 10-15 s. A continuous infusion "cocktail" containing verapamil, nitroglycerin, and heparin was administered to cool the RA system and avoid the slow flow phenomenon. After RA, predilatation using a semicompliant, noncompliant, or cutting balloon is left to the judgment of the operator in charge. If needed, several DESs or DCBs were applied to cover the whole stenotic segment. The DCB was dilated for at least 30-60 s at nominal pressure and used only in cases without flow-limiting dissection and severe vessel recoil. Upon procedure completion, intracoronary nitroglycerin was administered, and final angiography of the vessel was performed in at least two orthogonal views that showed the target site to be free of foreshortening or vessel overlap. Rescue DES implantation was recommended in the case of flow-limiting dissections after DCB treatment.
All patients in the RA/DCB group used paclitaxel-

Follow-up and endpoints
Follow-up data were collected by telephone interviews after PCI and through the hospital's electronic medical record system when patients returned for further consultation. In-hospital events included all-cause mortality, MI, and stroke. In-hospital MI was defined as an increase in cTn values of more than 5 times within 48 h of PCI, along with either new ischemic ECG changes, pathological Q wave development, or angiographic evidence of a flow-limiting complication. The primary endpoint of the study was major adverse cardiovascular and cerebrovascular events (MACCE) at the follow-up, which was defined as the composite of all-cause death, nonfatal myocardial infarction, target lesion revascularization (TLR), and stroke.

Statistical analysis
A paired-samples t test was used to compare data with regularly distributed quantitative data. With nonparametric data, the Wilcoxon matched-pair signed-rank test was used for analysis. The chi-squared test (Fisher's exact test) was used to examine qualitative data. The MACCEfree rates for the two groups were computed and graphically represented using the Kaplan-Meier method. The multivariable Cox regression analysis model was built by stepwise selection. All analyses were conducted by SPSS26. p < 0.05 was considered statistically significant.

Baseline clinical characteristics
A total of 318 patients who fulfilled the inclusion criteria were included in the study. Fifty-seven patients were treated with DCB after RA, and 261 were treated with DES. Baseline clinical characteristics for the two groups are shown in Table 1

Lesions and procedural characteristics
There were 332 consecutive lesions from 318 patients who underwent RA. Table 2 provides a summary of the lesions and procedural characteristics of the two groups. The number of left main and bifurcation lesions was larger in the RA/DES group, as were the number of implants, implant diameter, and total implant length. The utilization of IVUS/OCT, maximum burr size, and burr size and reference diameter were all significantly higher in the RA/DCB group.   Table 3.

Association between RA and MACCE
Both groups had the same Kaplan-Meier curve for the cumulative incidence of MACCE (Fig. 1).

Discussion
The present study suggests that the efficacy and safety of the RA/DCB strategy for CAC might be comparable to those of DES implantation, although significant differences in lesion features between the two groups at baseline. Cox regression analysis showed that DCB implantation was not associated with increased longterm MACCE of RA-PCI. Bifurcation lesions, SYNTAX scores, and the total length of device were independent predictors of MACCE. Based on the above results, it can be concluded that the severity of the lesions affects the long-term prognosis of patients who underwent RA-PCI. Although there is a significant correlation between CAC and coronary events, other prevalent cardiovascular risk factors do not appear indispensable for its progression. The genetic component thus appears to be important. By promoting the osteogenic differentiation of vascular smooth muscle cells, for instance, the β2-AR and G protein pathways may be crucial in forming calcified plaques [6]. Currently, severe CAC remains a challenge for successful PCI, which often requires the assistance of RA to modify the calcified plaque. Currently, RA followed by DES is the standard PCI strategy for CAC patients. However, there are certain limitations in the application of DES in CAC. First, heavily calcified plaques impair the trabecular meshwork, disrupting drug-polymer from the stent surface and reducing the success rate and long-term effectiveness of PCI [7]. Second, the existence of calcified nodules impedes complete stent expansion and accurate apposition, leading to an increased rate of in-stent restenosis and stent thrombosis [8]. Despite being rare, stent thrombosis may cause myocardial infarction (MI) or cardiac death [9]. Additionally, diffuse lesions are common in calcified vessels, which frequently need longer and numerous DES implanted to cover completely [10]. In this study, there were also many diffuse lesions, and the total length of devices in RA/DES group reached 52.16 ± 20.76 mm. Research shows that the implantation of lengthy stents may hinder the stented segment's ability to regain vasomotion, encourage neoatherosclerosis, and restrict access to revascularization [11]. The strategy of RA followed by DCB has numerous potential benefits in CAC. (1) RA can efficiently cleave calcified circles, lowering the danger of severe dissections brought by high-pressure dilation [12]. Moreover, elastic recoil does not easily occur in post-RA calcified vessels (mechanical support of the calcified circle). In previous studies, 6-27% of noncalcified vessels were implanted with rescue DES due to severe dissection or elastic recoil after DCB implantation [13]. (2) DCB-based PCI without leaving metal residues avoids the risk of stent thrombosis and leads to shorter dual antiplatelet therapy [14]. (3) In calcified vessels with diffuse long lesions, the use of DCB can avoid the implantation of lengthy stents and maintain access for future revascularization when needed. (4) For individuals with complex anatomical features such as ostial lesions, bifurcation lesions, and diffuse lesions, DCB implantation is typically more accessible and faster than DES implantation.
Previous studies on RA followed by DES showed that the target vessel revascularization (TLR) rate varied between 6.8 and 11.7% [15][16][17]. In this study, the TLR rate in the RA/DES group was 13.79%, which was slightly higher than that in previous reports, and the incidence of TLR in the RA/DCB group was 7.02%, similar to the  [18] showed that the TLR rate was extremely low (1.5% at 12 months), which may be related to the low followup rate of angiography. Three small sample studies from Japan showed that the TLR rate is 6-16%, which is close to the results of our study [12,19,20]. Currently, there are few studies on the application of DCBs in CAC. A retrospective study revealed no significant difference in MACCE, TLR rate, and late lumen loss between the calcified and noncalcified groups after DCB implantation [13]. In terms of safety, it is worth mentioning that in this study, DCBs were implanted in only a few patients, while DESs were implanted in more patients with severe dissection or high residual stenosis. In the RA/DCB group, two patients underwent rescue DES implantation after DCB implantation due to severe dissection, and no acute occlusion occurred. Compared with the RA/DES group, there was no significant difference in complications and in-hospital adverse events. Therefore, we believe that DCB implantation is safe when RA effectively relieves the burden of calcified plaque without causing severe dissection. Coronary angiography only offers two-dimensional pictures, which places various limitations in evaluating calcified lesions. Intracoronary imaging modalities such as OCT and IVUS are three-dimensional imaging tools that can precisely evaluate calcified lesions and display the intima, media, and adventitia of coronary vessels [21]. Additionally, it can offer comprehensive instructions for choosing the right rotary burr size and developing an RA scheme. Studies show that intracoronary imaging guidance can improve the success rate of PCI, obtain more significant luminal gain and improve long-term prognosis [22]. The predilation requirements for DCBs are higher than those for DESs. Intracoronary imaging mode can accurately evaluate the predilate results, select the appropriate DCB size and accurately position the DCB to achieve complete adhesion and coverage of lesions. In addition, dissection after DCB implantation is usually inevitable. Mild to moderate dissection that does not affect blood perfusion is usually safe, and it can encourage the drug to penetrate the vessel wall, thus promoting long-term lumen enlargement [23]. However, for severe dissection, due to the lack of stent support, the dissection may expand distally and cause vascular occlusion. Coronary angiography is less sensitive to dissection, often missed or underestimated [24]. Intravascular imaging can sensitively detect severe dissection that can lead to acute vascular occlusion and guide the implantation of rescue stents [25]. In this study, approximately 58.62% of patients in the RA/ DCB group received PCI under the guidance of intracoronary imaging, which was higher than the 38.69% in the RA/DES group. It is worth mentioning that in the RA/DCB group, after DCB implantation, IVUS detected a high-risk dissection that was not found by angiography, and then a rescue DES was implanted.
There are some limitations to this research. First, this was a single-center retrospective study in which the operator decided on the implantation of DCB or DES after RA. Second, this study only compared the curative effects of DCB and DES alone after RA but did not include patients who used DCB and DES simultaneously. Third, baseline lesion characteristics was quite different between DCB and DES groups, DCB tended to be used for simpler cases in severe calcified lesions. Fourth, the number of patients in the DCB group was small, and the number of patients who received coronary angiography follow-up after PCI was limited. In the future, more large-sample randomized controlled studies are expected to clarify the safety and effectiveness of RA combined with DCB in treating severe coronary artery calcification.